We have identified a novel survival pathway within tumor vascular endothelium that enhances the therapeutic effects of ionizing radiation. Considering that radiation therapy is the primary modality of treatment for unresectable lung carcinoma, improving the efficacy of this treatment is important to improve the cure rate of lung cancer patients. In this regard, we have collaborated with several pharmaceutical companies that are developing small compounds that inhibit specific enzymes within the tumor endothelium. We will only investigate compounds that have entered or will enter clinical studies within the next 3 years. These compounds include SU5416 and SU6668 (Sugen) and PTK87/2K222584 (Novartis). These compounds inhibit receptor tyrosine kinases and downregulate the survival pathway within the tumor endothelium. These compounds will also enter clinical studies through the clinical core in this lung cancer SPORE application. An example of the success in this endeavor is the clinical protocol investigating SU5416 with radiation in a neoadjuvant lung cancer study. We anticipate additional studies with other compounds and future phase III trials. In addition to this translational approach, we will also investigate the mechanisms by which Flk-1 antagonists enhance the therapeutic effects of radiation. We will study the PI3 kinase and Akt/PKB signal transduction pathways. Our preliminary findings indicate that inhibition of this pathway enhances radiation-induced apoptosis in the vascular endothelium. We have entered into a material transfer agreement with ICOS, Inc. ICOS has identified several small compounds that inhibit specific isoforms of PI3 kinase. We will determine which of these compounds is most effective in enhancing the therapeutic effects of radiation in lung cancer models in mice. These compounds will then be developed at ICOS to enhance the pharmacokinetics and minimize toxicity. The same approach will be taken with Akt inhibitors as they are developed. In summary, findings from these preclinical studies will assist us in the design of phase I and feasibility studies in the clinic through the clinical core in this SPORE application. In addition, our close collaboration with pharmaceutical companies will ensure that these compounds move rapidly into clinical trials.